The goal of this proposal is to discover signaling and epigenetic cues that direct the formation of endocrine cell progenitors and definitive beta cells in embryonic development and adult regenerative contexts, and to promote the application of such advances within the Beta Cell Biology Consortium (BCBC) to ameliorate type I diabetes (T1D). To date, most research in the beta cell development field has focused on transcription factors. Recent studies from our laboratories have revealed a complex and dynamic network of signals that induce PDX1+ pancreatic progenitors from undifferentiated endoderm cells, as well as conditions in adult tissues in which beta cells can be generated from non-beta cells. Yet the specific combination of extracellular cues that induce PDX1+ pancreatic progenitors to make NGN3+ endocrine progenitors in the embryo, the cues that induce NGN3+ cells to make definitive insulin+ beta cells, and the cues that induce the formation of new beta cells from non-beta cells in adult regeneration, remain to be defined. In addition, little is known about the chromatin modifications that enable the paths to the beta cell. We note that the extracellular inducers of cell differentiation usually are soluble molecules, that the cellular response pathways to such inducers usually are mediated by enzymes, and that many of the resulting modifications of chromatin usually are mediated by enzymes. Thus our plan to identify signals and chromatin transitions necessary to promote endocrine and beta cell differentiation and regeneration will allow the use of small molecule modifiers of enzyme activity to modulate the formation and growth of beta cells from stem cells and other progenitors, without having to resort to genetic modification. To provide novel directions for the field, our primary emphasis is on previously unappreciated signals and response mechanisms and new types of beta cell progenitors. By sharing technology and information from our work within the BCBC consortium, collaborators investigating the generation of beta cells from human embryonic stem cells, the field at large, and centers of excellence running clinical trials for T1D, our studies will be translated to help cure diabetes. PUBLIC HEALTH RELEVANCE: Our emphasis on identifying unanticipated signals and epigenetic cues that promote the development of pancreatic progenitors to beta cells is intended to provide novel directions for the field to generate beta cells for type I diabetics from embryonic stem cells and from new cell sources that arise in the injured pancreas, without having to resort to genetic modification of the cells.